Various publications, including patents, published patent applications, technical articles, scholarly articles, and gene or protein accession numbers are cited throughout the specification. Each of these materials is incorporated by reference herein, in its entirety and for all purposes.
CD38 is a 46 kDa type II transmembrane glycoprotein that is involved in transmembrane signaling and cell adhesion. It is also known as cyclic ADP ribose hydrolase because it can transform NAD+ and NADP+ into cADPR, ADPR and NAADP, depending on extracellular pH. These products induce Ca2+-mobilization inside the cell, which can lead to tyrosine phosphorylation and activation of the cell. CD38 is also a receptor that can interact with a ligand, CD31. Activation of receptor via CD31 leads to intracellular events including Ca2+ mobilization, cell activation, proliferation, differentiation and migration.
CD38 is expressed at high levels on the surface of multiple myeloma cells, in most cases of T- and B-lineage acute lymphoblastic leukemias (ALL), some acute myelocytic leukemias, follicular center cell lymphomas and T lymphoblastic lymphomas. CD38 is also expressed on B-lineage chronic lymphoblastic leukemia (B-CLL) cells. In some cases, B-CLL patients presenting with a CD38+ clone are characterized by an unfavorable clinical course with a more advanced stage of disease, poor responsiveness to chemotherapy and shorter survival time.
Interferons, and in particular IFN-alpha, are able to increase apoptosis and decrease proliferation of certain cancer cells. IFN-alpha has been approved by the FDA for the treatment of several cancers including melanoma, renal cell carcinoma, B cell lymphoma, multiple myeloma, chronic myelogenous leukemia (CML) and hairy cell leukemia. A direct effect of IFN-alpha on the tumor cells is mediated by the IFN-alpha binding directly to the type I IFN receptor on those cells and stimulating apoptosis, terminal differentiation and/or reduced proliferation. Further, amongst the indirect effects of IFN-alpha on non-cancer cells is the ability of IFN-alpha to stimulate the immune system, which may produce an additional anti-cancer effect by causing the immune system to reject the tumor. IFN-alpha also exhibits the ability to inhibit tumor angiogenesis and, thus, may inhibit tumor growth by metabolic starvation.
The direct anti-tumor activities of IFN-alpha are mediated by type I interferon receptors on the surface of the cancer cells which, when stimulated, initiate various signal transduction pathways leading to reduced proliferation and/or the induction of terminal differentiation or apoptosis. The type I interferon receptor is, however, also present on most non-cancerous cells. Activation of the type I receptor on non-cancerous cells by IFN-alpha causes the expression of numerous pro-inflammatory cytokines and chemokines, leading to undesirable systemic toxicity. Such toxicity may cause severe flu-like symptoms, which prevents the dosing to a subject of IFN-alpha at levels that exert the maximum anti-proliferative and pro-apoptotic activity on the cancer cells.
In general, IFN may be targeted to cancer cells, for example, by linking it with a targeting antibody or targeting fragment thereof. While this approach may result in an increase in activity of the IFN against cancer cells, it does not completely address the issue of undesired activity of the IFN on healthy cells. Fusing IFN-alpha to the C-terminus of the heavy chain of an IgG may, for example, prolong the half-life of the IFN alpha, which may prolong undesirable adverse events. Accordingly, there exists a need to improve the systemic toxicity profile of interferon while retaining one or more of its anti-tumor effects.
Both lenalidomide and pomalidomide are small molecule immune modulators, and derivatives of the anti-multiple myeloma drug thalidomide. Both lenalidomide and pomalidomide are used in the treatment and maintenance of certain cancers, including multiple myeloma and lymphoma. In many cases, tumors which are initially sensitive to lenalidomide or pomalidomide become resistant or refractory to these agents. In other cases, tumors do not respond to lenalidomide or pomalidomide therapy. There is a need in the art to overcome lenalidomide or pomalidomide-resistance or to enhance lenalidomide or pomalidomide activity, and potentially provide therapies whereby non-responsive patients may come to respond to lenalidomide or pomalidomide therapy.